Three years into a global pandemic, we continue to see Covid-19 spread worldwide and are just beginning to understand the long-term consequences of the novel virus. Understanding the impact of sex hormones on both immune and inflammatory processes may provide us with clinical importance for both acute and long Covid. Older adults are at an increased risk of mortality from Covid-19; the protective effect of younger age occurs in both males and females; however, women have been shown to mount a more robust immune response than men to most infectious diseases.1,2 The female immune system is more efficient and effective in responding to pathogens like viruses. This immune-protective effect is influenced primarily by estrogen; therefore, there is an age-related decline in this effect in postmenopausal women.3 For coronaviruses in particular, we have seen women have higher survival rates than men.
How Does Covid-19 Effect Women's Hormones
It is now widely accepted that the most significant pathway through which Covid-19 is hypothesized to damage the tissues is by way of inflammation.4 The sex difference in inflammatory response between men and women is thought to be primarily determined by sex hormones.5 Estrogen, one of the predominant sex hormones in women, has an anti-inflammatory effect in premenopausal women. Immune-mediated inflammatory compounds are inhibited by the cyclical changes in estrogen throughout the menstrual cycle. Low estrogen levels can exacerbate inflammation, which can explain many pro-inflammatory states that postmenopausal women suffer from.
Covid - 19 And Women's Menstrual Cycle
If women inherently have hormone-mediated immune protection, why are we seeing higher rates of hormone-related concerns post-covid infection and even long Covid? Since the beginning of the pandemic, there have been growing discussions on online forums and social media attributing menstrual cycle changes to Covid infection. Discussions about changes in menstrual duration, frequency, and regularity, as well as heavier bleeding, increased menstrual pain and worsened premenstrual syndrome (PMS) were all relevant topics. Furthermore, a recent study showed that 53% of 749 women surveyed, reported changes in PMS and cycle duration.6 Not only are clinicians seeing higher rates of menstrual cycle complaints, but research is showing that these changes are significant enough that both women and their healthcare providers should be aware of the implications of acute infection and long-term complications.
To give a brief understanding of the menstrual cycle, the average menstrual cycle is about 28 days, with ovulation occurring halfway through around day 14. As the egg is released during ovulation, a follicle is formed in the ovary that produces a gland that makes and releases progesterone. Progesterone supports the uterus for pregnancy if the egg happens to be fertilized. If no fertilization occurs, progesterone and estrogen decline about one week before menses. The drop in hormones often triggers PMS, or worse, premenstrual dysphoric disorder (PMDD), a severe form of PMS. It isn’t always that women with PMS or PMDD have a hormonal imbalance, but rather, they are more sensitive to the change in hormones.
Covid And PMS And PMDD
A small amount of evidence suggests this sensitivity may be due to genetic susceptibility.7 However, decades of clinical data support that PMS and PMDD aren’t purely biological or genetic. The degree to which premenstrual hormone changes will affect someone is also informed by the person’s perceived stress and mental and emotional well-being. It is undeniable that these last three years have led to tremendous amounts of stress on individuals and families. Elevated and persistent stress encourages the release of cortisol from the adrenal glands. Unregulated cortisol can lead to suppression of sex hormone production, which can cause irregular menstrual cycles, infrequent or abnormal ovulation, or can cause the cycle to stop altogether.
It is unfortunate that menstruation has been omitted from the majority of large-scale Covid-19 studies, which makes it unclear how many women have experienced menstrual cycle changes. The hormones that regulate the menstrual cycle interact with the immune and vascular systems. These interactions, in turn, influence menstrual duration, amount of bleeding, and severity of PMS via the hypothalamic-pituitary-ovarian-endometrial axis.8 The most common menstrual complaints post-covid infection include infrequent menstruation, irregular menstruation, and heavy or prolonged bleeding. At the level of the hypothalamus and pituitary (aka the brain), we can deduce that Covid-induced stress and Covid-induced illness may cause the brain to release lower amounts of hormone, resulting in ovarian dysfunction and transient menstrual irregularities.9 Moreover, Covid may directly impact the production of estrogen and progesterone from the ovaries, triggering dysfunction and abnormal bleeding. Heavy and prolonged bleeding may be due to the impact of Covid infection on the uterus's inflammatory processes before and during menses.
Hormone Changes May Increase Covid Symptoms
Conversely, hormonal changes during the menstrual cycle may also exacerbate Covid-19 symptoms. For those suffering from long Covid, cyclical relapse in symptoms prior to or during menstruation is not uncommon.10 Our understanding of the long-term impact of acute Covid-19 infection is limited. A recent study on long Covid showed that women under the age of 50 were five times less likely to report feeling recovered, were more likely to have disability from Covid, seven times more likely to report breathlessness, and twice as likely to report worsening fatigue than men of the same age.11
Menopause Hormone Changes And It's Effect On Covid-19
The onset of menopause is another time in a woman’s life in which long Covid symptoms have been documented to be more frequent or severe. Even transient viral-induced disruption to ovarian hormone production could acutely exacerbate symptoms of perimenopause and menopause. There happens to be a lot of overlap between long Covid symptoms and symptoms related to perimenopause and menopause. These symptoms include fatigue, heart palpitations, cognitive impairment, and sleep disruption. It is important for clinicians to evaluate for a proper diagnosis of perimenopause or menopause as it creates the opportunity to treat these symptoms with safe and effective hormone replacement therapy (HRT). Not only does HRT reduce some women’s risk of cardiovascular disease, type 2 diabetes, osteoporosis, obesity, and dementia, but it may also offer hormone-mediated immune protection against acute and chronic viruses.
It remains unclear why females have worse outcomes. Possible explanations include the fact that women are more likely to be working in industries where exposure to Covid-19 is higher; women are more likely to survive severe acute disease than men, therefore, worsening long-term outcomes; and perhaps, men felt less comfortable disclosing their symptoms.11 One theory for long Covid is that particles of the virus hide in remote reservoirs of the body for many months.12 These particles have been found in almost every tissue, including the brain, uterus, and kidneys. Due to the strong reaction that women tend to have to viral infections, it is thought that the viral reservoirs trigger cycles of chronic inflammation, causing symptoms like fatigue, pain, and brain fog. Another theory is that the virus may have triggered an autoimmune response wherein the immune system produces its own antibodies known as autoantibodies.13 Studies have identified increased levels of more than 100 different autoantibodies in Covid-19 patients. If these autoantibodies remain in the blood of a person with long Covid over an extended period of time, it may explain many of the expected long Covid symptoms.
It is clear that more research is needed for why women have higher rates of long Covid. Since women tend to mount a more robust immune response to acute infection than men and because women have higher rates of autoimmune disease, it can be extrapolated that this complex immune response is triggering long Covid. Furthermore, due to the intricate interplay between sex hormones, stress hormones, and the immune system, women are documenting menstrual irregularities and increased PMS post-Covid infection. As more research is funded, hopefully, we will receive clarity on the impact that Covid-19 has on the female hormone system.
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Georgie Bruinvels, Esther Goldsmith, Richard C. Blagrove, Dan Martin, Laurence Shaw, Jessica Piasecki. How lifestyle changes within the COVID-19 global pandemic have affected the pattern and symptoms of the menstrual cycle. medRxiv 2021.02.01.21250919; doi:https://doi.org/10.1101/2021.02.01.21250919
Dubey N, Hoffman JF, Schuebel K, Yuan Q, Martinez PE, Nieman LK, Rubinow DR, Schmidt PJ, Goldman D. The ESC/E(Z) complex, an intrinsic cellular molecular pathway differentially responsive to ovarian steroids in Premenstrual Dysphoric Disorder, Molecular Psychiatry, January 3, 2016, doi:10.1038/mp.2016.229.
Bertone-Johnson ER, Ronnenberg AG, Houghton SC et al. Association of inflammation markers with menstrual symptom severity and premenstrual syndrome in young women. Hum Reprod 2014;29:1987–94.
Gemma C Sharp, Abigail Fraser, Gemma Sawyer, Gabriella Kountourides, Kayleigh E Easey, Gemma Ford, Zuzanna Olszewska, Laura D Howe, Deborah A Lawlor, Alexandra Alvergne, Jacqueline A Maybin, The COVID-19 pandemic and the menstrual cycle: research gaps and opportunities, International Journal of Epidemiology, Volume 51, Issue 3, June 2022, Pages 691–700, https://doi.org/10.1093/ije/dyab239
Davis HE, Assaf GS, McCorkell L et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine 2021;38:101019.
Sigfrid L, Drake TM, Pauley E, Jesudason EC, Olliaro P, Lim WS, et al. Long Covid in adults discharged from UK hospitals after Covid-19: A prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol. Lancet Reg Health - Eur. 2021 Aug.
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Michael Ehrenfeld, Angela Tincani, Laura Andreoli, Marco Cattalini, Assaf Greenbaum, Darja Kanduc, Jaume Alijotas-Reig, Vsevolod Zinserling, Natalia Semenova, Howard Amital, Yehuda Shoenfeld,Covid-19 and autoimmunity, Autoimmunity Reviews, Volume 19, Issue 8, 2020, 102597, ISSN 1568-9972, https://doi.org/10.1016/j.autrev.2020.102597.